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Structural investigations on the structure-function relationships of Aurora Kinases


Aurora protein kinases belong to the family of serine/threonine protein kinases. They are evolutionarily conserved enzymes that regulate different aspects of cell division. In vertebrates, there exists three Aurora kinases namely, Aurora A, Aurora B and Aurora C. In contrast, the C. elegans and D. melanogaster genomes encode only for two Aurora orthologues, and the S. cerevisiae genome for a single one. Aurora kinases differ in length and sequence of the amino terminal domain (non-catalytic domain), but show considerable similarity in the carboxy-terminal catalytic domain. Interestingly, even in the presence of high sequence similarity the three Aurora kinases are localized in distinct locations and perform different functions.

Aurora A is shown to play a major role in centrosome separation, centrosome maturation and in the stabilization of mitotic spindle assembly, while the Aurora B is important in the regulation of kinetochore-microtubule interactions. The function of Aurora A is conserved in human, Xenopus, Drosophila and C. elegans. Recent studies that include the crystallographic studies from the host laboratory showed the role of TPX2, an activator of human Aurora A in molecular recognition and regulation. Although the function of Aurora A is con served in human, Xenopus, Drosophila and C. elegans, there is no apparent homologue of TPX2 in their respective genomes. In a similar note, the Auroras A and B share very high sequence identity but their respective activators TPX2 and INCENP do not show a ny reasonable sequence similarity.

The proposed project aims to understand the molecular machanism involved in the activation and regulation of Aurora A from C.elegans and Drosophila and of human Aurora B mainly using X-ray crystallographic methods. Since, Aurora proteins are oncogens, the structural information derived from this study would help in designing specific inhibitors to block their activation.

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